The Ras oncogene is one of the most frequently mutated oncogenes in human cancer. Approximately 30 percent of human cancers contain activated Ras mutations. Extensive efforts have been made to identify Ras inhibitor as a putative cancer therapy with the most promising progress of farnesyl transferase inhibitor. Farnesylation of Ras is essential for its biological functions. However, many small GTPases, which play important roles in cellular functions, also require farnesylation or isoprenylation. Therefore, these inhibitors may have none specific effects due to inhibition of other small GTPases. A major long-term goal of OncoImmune is to develop therapeutic agents for treatment of cancers. The main goal of this proposal is to demonstrate that GDP-bound Ras mutant, RasN17N69, can be used to inhibit cancer cell growth in vitro and in vivo. This proposal is based on our novel observations that RasN17N69 inhibits cell transformation but not growth of normal cells. Furthermore, the proposal uses a new technology of protein transduction to test this hypothesis in vitro and in vivo. The following specific aims will be accomplished in this proposal. 1. To demonstrate that GDP-bound mutant RasN17N69 can suppress transforming phenotypes of tumor cells. 2. To provide evidence that RasN17N69 can inhibit tumor growth in animal model. PROPOSED COMMERCIAL APPLICATION: Cancer is one of the leading causes of mortality in the US. Approximately 30% of human cancers contain activating mutation of Ras. This project will provide critical information that RasN17N69 can be used in treatment of cancers containing Ras mutation. The proposal is based on a novel concept that the GDP-bound RasN17N69 can reverse transformation by oncogenic Ras mutation. The potential commercial application and therapeutic benefits are far reaching.